Abstract
Marked changes in energy substrate utilization occur during the progression of congestive heart failure (CHF) where fatty acid utilization, as the primary source of cardiac energy, is severely diminished, oxidative phosphorylation is down-regulated, and glucose uptake and utilization increase. Neither the signaling events or the molecular basis for the shift in substrate utilization have yet been elucidated. This study was designed to examine in the canine model of paced-induced CHF, the potential role of the Akt pathway in signaling the metabolic transitions central to progression to heart failure. Myocardial Akt levels were elevated in early heart failure (after 1–2 weeks of pacing) accompanied by increased levels of oxidative stress, cytokine tumor necrosis factor-α (TNF-α) and free fatty acid accumulation, reduced activity levels of mitochondrial respiratory complexes III and V and apoptosis initiation. At severe heart failure (3–4 weeks of pacing), there was significant further increase in myocardial apoptosis, with pronounced decline in myocardial Akt kinase activity. At this later stage, there were no further changes in free fatty acid accumulation, complex V activity or in oxidative stress levels indicating that these changes primarily occurred in the earlier stage of evolving heart failure. In contrast, during severe heart failure, both the reduction in complex III activity and increase in TNF-α level became more pronounced. Our data provide critical support for the hypothesis that the Akt signaling pathway is a contributory element in the early signaling events leading to the progression of pacing-induced heart failure, accompanying the shift in substrate utilization. (Mol Cell Biochem 268: 103–110, 2005)
Similar content being viewed by others
References
Moe GW, Armstrong P: Pacing-induced heart failure: A model to study the mechanism of disease progression and novel therapy in heart failure. Cardiovasc Res 42: 591–599, 1999
Kajstura J, Zhang X, Liu Y, Szoke E, Cheng W, Olivetti G, Hintze TH, Anversa P: The cellular basis of pacing-induced dilated cardiomyopathy. Myocyte cell loss and myocyte cellular reactive hypertrophy. Circulation 92: 2306–2317, 1995
Bradham WS, Moe G, Wendt KA, Scott AA, Konig A, Romanova M, Naik G, Spinale FG: TNF-α and myocardial matrix metalloproteinases in heart failure: Relationship to LV remodeling. Am J Physiol Heart Circ Physiol 282: H1288–H1295, 2002
Marin-Garcia J, Goldenthal JM, Moe GW: Abnormal cardiac and skeletal muscle mitochondrial function in pacing induced cardiac failure. Cardiovasc Res 52: 103–110, 2001
Cha YM, Dzeja PP, Shen WK, Jahangir A, Hart CY, Terzic A, Redfield MM: Failing atrial myocardium: Energetic deficits accompany structural remodeling and electrical instability. Am J Physiol Heart Circ Physiol 284: H1313–H1320, 2003
Kataoka K, Nohara R, Hosokawa R, Hirai T, Okuda K, Li-Guang C, Fujibayashi Y, Fujita M, Konishi J, Sasayama S: Myocardial lipid metabolism in compensated and advanced stages of heart failure: Evaluation by canine pacing model with BMIPP. J Nucl Med 42: 124–129, 2001
Suematsu N, Tsutsui H, Wen J, Kang D, Ikeuchi M, Ide T, Hayashidani S, Shiomi T, Kubota T, Hamasaki N, Takeshita A: Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 107: 1418–1423, 2003
Condorelli G, Morisco C, Latronico MV, Claudio PP, Dent P, Tsichlis P, Condorelli G, Frati G, Drusco A, Croce CM, Napoli C: TNF-alpha signal transduction in rat neonatal cardiac myocytes: Definition of pathways generating from the TNF-alpha receptor. FASEB J 16: 1732–1737, 2002
Konishi H, Matsuzaki H, Tanaka M, Takemura Y, Kuroda S, Ono Y, Kikkawa U: Activation of protein kinase B (Akt/RAC-protein kinase) by cellular stress and its association with heat shock protein Hsp27. FEBS Lett 410: 493–498, 1997
Hiraoka E, Kawashima S, Takahashi T, Rikitake Y, Kitamura T, Ogawa W, Yokoyama M: TNF-alpha induces protein synthesis through PI3-kinase-Akt/PKB pathway in cardiac myocytes. Am J Physiol Heart Circ Physiol 280: H1861–H1868, 2001
Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J Jr: Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99: 12333–12338, 2002
Sugden PH: Signaling pathways activated by vasoactive peptides in the cardiac myocyte and their role in myocardial pathologies. J Card Fail 8: S359–S369, 2002
Clerk A, Sugden PH: Activation of protein kinase cascades in the heart by hypertrophic G protein-coupled receptor agonists. Am J Cardiol 83: 64H–69H, 1999
Matsui T, Li L, del Monte F, Fukui Y, Fukui Y, Franke TF, Hajjar RJ, Rosenzweig A: Adenoviral gene transfer of activated phospatidyl inositol 3-kinase and Akt inhibits apoptosis of hypoxic cardiomyocytes in vitro. Circulation 100: 2373–2379, 1999
McMullen JR, Shioi T, Huang WY, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S: The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase (p110alpha) pathway. J Biol Chem 279: 4782–4793, 2004
Soltys CL, Buchholz L, Gandhi M, Clanachan AS, Walsh K, Dyck JR: Phosphorylation of cardiac protein kinase B is regulated by palmitate. Am J Physiol Heart Circ Physiol 283: H1056–H1064, 2002
Leslie NR, Bennett D, Lindsay YE, Sterwart H, Gray A, Downes CP: Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 22: 5501–5510, 2003
Moe GW, Angus C, Howard RJ, Parker TG, Armstrong PW: Evaluation of indices of left ventricular contractility and relaxation in evolving canine experimental heart failure. Cardiovasc Res 26: 362–366, 1992
Howard RJ, Moe GW, Armstrong PW: Sequential echocardiographic-Doppler assessment of left ventricular remodelling and mitral regurgitation during evolving experimental heart failure. Cardiovasc Res 25: 468–474, 1991
Armstrong PW, Moe GW: The development of and recovery from pacing-induced heart failure. In: F.G. Spinale (ed). Pathophysiology of Tachycardia-Induced Heart Failure. Futura Publishing Company, Armonk, NY, 1996, pp 45–59
Luo XP, Yazdanpanah M, Bhooi N, Lehotay DC: Determination of aldehydes and other lipid peroxidation products in biological samples by gas chromatography–mass spectroscopy. Anal Chem 228: 294–298, 1995
Song W, Lu X, Feng Q: Tumor necrosis factor-alpha induces apoptosis via inducible nitric oxide synthase in neonatal mouse cardiomyocytes. Cardiovasc Res 45: 595–602, 2000
Moe GW, Naik G, Konig A, Lu X, Feng Q: Early and persistent activation of myocardial apoptosis, bax and caspases: Insights into mechanisms of progression of heart failure. Pathophysiology 8: 183–192, 2002
Liu Y, Cigola E, Cheng W, Kajstura J, Olivetti G, Hintze TH, Anversa P: Myocyte nuclear mitotic division and programmed myocyte cell death characterize the cardiac myopathy induced by rapid ventricular pacing in dogs. Lab Invest 73: 771–787, 1995
Kumar D, Lou H, Singal PK: Oxidative stress and apoptosis in heart dysfunction. Herz 27: 662–668, 2002
Datta SR, Brunet A, Greenberg ME: Cellular survival: A play in three Akts. Genes Dev 13: 2905–2927, 1999
Matsui T, Nagoshi T, Rosenzweig A: Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2: 220–223, 2003
Pham FH, Sugden PH, Clerk A: Regulation of protein kinase B and 4E-BP1 by oxidative stress in cardiac myocytes. Circ Res 86: 1252–1258, 2000
Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH: Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res 83: 969–979, 1998
Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA: Impaired myocardial fatty oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 106: 606–612, 2002
Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP: Fatty acid oxidation enzyme gene expression is down regulated in the failing heart. Circulation 94: 2837–2842, 1996
Cook SA, Matsui T, Li L, Rosenzweig A: Transcriptional effects of chronic Akt activation in the heart. J Biol Chem 277: 22528–22533, 2002
Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR: Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278: 39422–39427, 2003
Qin S, Chock PB: Implication of phosphatidylinositol 3-kinase membrane recruitment in hydrogen peroxide-induced activation of PI3K and Akt. Biochemistry 42: 2995–3003, 2003
Gudz T, Tserng K, Hoppel CL: Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272: 24154–24158, 1997
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241, 1997
Liu W, Akhand AA, Takeda K, Kawamoto Y, Itoigawa M, Kato M, Suzuki H, Ishikawa N, Nakashima I: Protein phosphatase 2A-linked and unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal. Cell Death Differ 10: 772–781, 2003
Kageyama K, Ihara Y, Goto S, Urata Y, Toda G, Yano K, Kondo T: Overexpression of calreticulin modulates protein kinase B/Akt signaling to promote apoptosis during cardiac differentiation of cardiomyoblast H9c2 cells. J Biol Chem 277: 19255–19256, 2002
Neumann J, {Eschenhagen T, Jones LR, Linck B, Schmitz W, Scholz H, Zimmermann N: Increased expression of cardiac phosphatases in patients with end-stage heart failure. J Mol Cell Cardiol 29: 265–272, 1997
Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen YT, Shannon RP: The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res 61: 297–306, 2004
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ananthakrishnan, R., Moe, G.W., Goldenthal, M.J. et al. Akt signaling pathway in pacing-induced heart failure. Mol Cell Biochem 268, 103–110 (2005). https://doi.org/10.1007/s11010-005-3699-3
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11010-005-3699-3